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PLASMA LEVELS OF ACTVIN A SIGNIFICANTLY INCREASED IN PATIENTS WITH COLORECTAL CANCER COMPARED TO BENIGN DISEASE PATIENTS
Hmc Shantha Kumara
*1, Hiromichi Miyagaki
2, Yi-Ru Chen
1, Neil Mitra
1, Elizabeth Nilsson Sjolander
1, Xiaohong Yan
3, Vesna Cekic
1, Richard L. Whelan
11Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY; 2Department of Surgery, Otemae Hospital, Osaka, Chuo-ku, Osaka, Japan; 3Department of Pathology and Cell Biology, Columbia University Medical Center, Vanderbilt Clinic, New York, NY
Introduction: Activin A (ActA) is part of the TGF-? family. This protein plays a role in the regulation of various physiological processes including cell growth, differentiation, wound healing, inflammation, and immune responses. ActA expression varies in different tissues and cell types; it transmits signals through transmembrane serine/threonine kinase receptors. This interaction activates the SMAD signaling cascade. ActA is a critical mediator of VEGF-induced angiogenesis and plays a role in FGF-2-induced capillary formation. ActA is overexpressed in many cancers including colorectal cancer (CRC), and increased plasma levels correlate with poorer prognosis. A preliminary study that assessed 44 colorectal cancer (CRC) and 37 benign colonic disease (BCD) patients (pts) showed higher plasma ActA levels in CRC pts. The present study assesses plasma Preop ActA levels in a notably larger cohort of CRC BCD pts.to further investigate the potential of ActA as a prognostic biomarker for CRC.
Method: Patients (pts.) who underwent for CRC or BCD and were participants in an IRB approved tissue and data bank for whom PreOp plasma samples were available were included. Clinical and pathologic data were evaluated. Blood samples were collected, processed and stored at -80
oC. ActA levels in preop plasma samples were determined via ELISA in duplicate and reported as median + 95%CI (ng/ml). ActA expression in self paired CRC and normal tissue specimens in a subpopulation was assessed by QRT-PCR. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to assess plasma ActA as a diagnostic tool. Immunohistochemistry (IHC) was performed on subset of tumors. (Tumor/normal pairs). The Mann-Whitney test was used for statistical analysis (sig. p<0.05).
Results: A total of 147 CRC (78% colon, 22% rectal) and 142 BCD pts (adenoma 39%, diverticulitis 55%, other 6%) were studied (male/female ratios similar, CRC pts were older (p<0.001)). The CRC stage (Stg) distribution was: Stg 1, 22%; Stg 2, 37%; Stg 3, 27%; and Stg 4, 14%. The median plasma ActA levels were significantly higher in the CRC (370.9, CI: 349.2, 413.1) vs. the BCD patients (251.8, CI: 216.5, 277.9; P=< 0.001. Plasma ActA levels were higher in Stg 4 pats vs. Stg 1,2,3 pts (p<0.001). The AUC value for ROC curve was 0.770(sensitivity 78%, specificity 63%). All CRC samples (n=18) tested demonstrate elevated ActA expression vs. normal tissue. IHC confirmed ActA expression in CRC tumors.
Conclusion: The CRC median ActA level vs the BCP pts was 47% higher; Stg 4 levels were 78% higher than Stg 1 pts. The ROC curve is mildly promising as regards plasma ActA levels as a CRC detection biomarker. The source of the added ActA increase may be tumor, stromal or inflammatory cells. Elevated ActA may support neoangeogenesis and growth of residual tumor. Further study is warranted.
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